367-21-5

Basic information

• Product Name: 3-Chloro-4-fluoroaniline
• Synonyms: 3-Chlor-4-fluoranilin;3-CHLORO-4-FLUOROANILINE A;3-CHLORO-4-FLUOROANILINE B;3-CHLORO-4-FLUOROANILINE, 99.5+%;3-CHLORO-4-FLUOROANILINENORFLOXACIN;3-CHLORO-4-FLUOROANILINE pure;3-Chloro-4-fluoroanaline;3-Chloro-4-fluoroanaline 1g [367-21-5]
• CAS NO: 367-21-5
• Molecular Formula: C₆H₅ClFN
• Molecular Weight: 145.56
• EINECS: 206-682-8
• Product Categories: Drug Intermediates;Anilines, Aromatic Amines and Nitro Compounds;Fluorobenzene;C2 to C6;Nitrogen Compounds;ChloroChemical Class;FluoroMore...Close...;Alpha Sort;Amines;Analytical Standards;AromaticsChemical Class;AromaticsVolatiles/ Semivolatiles;C;CAlphabetic;CHChemical Class;Chemical Class;Halogenated;Aniline series;API Intermediate;Furans ,Coumarins
• Mol File: 367-21-5.mol
• Article Data: 27

Chemical Properties

• Melting Point: 42-44 °C(lit.)
• Boiling Point: 227-228 °C(lit.)
• Flash Point: >230 °F
• Appearance: Beige to brown/Crystalline Solid
• Density: 1,226 g/cm3
• Vapor Pressure: 0.0522mmHg at 25°C
• Refractive Index: 1,54-1,542
• Storage Temp.: Store below +30°C.
• Solubility: 10g/l
• PKA: 3.60±0.10(Predicted)
• Water Solubility: 10 g/L (20 ºC)
• Stability: Stable. Incompatible with strong oxidizing agents, acids, acid chlorides, acid anhydrides, chloroformates. May be air-sensitive.
• BRN: 1562786
• CAS DataBase Reference: 3-Chloro-4-fluoroaniline(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Chloro-4-fluoroaniline(367-21-5)
• EPA Substance Registry System: 3-Chloro-4-fluoroaniline(367-21-5)

Safety Data

• Hazard Codes: T,Xi,Xn
• Statements: 23/24/25-33-36/37/38-20/21/22
• Safety Statements: 36/37/39-45-26
• RIDADR: UN 2811 6.1/PG 2
• WGK Germany: 2
• F: 9-23
• TSCA: T
• HazardClass: TOXIC
• PackingGroup: III
• Hazardous Substances Data: 367-21-5(Hazardous Substances Data)

Usage

Chemical Properties

dark purple to black solid

General Description

The exposure of workers to 3-chloro-4-fluoroaniline (CFA) was monitored by an HPLC method.

InChI:InChI=1/C6H5ClFN/c7-5-2-1-4(9)3-6(5)8/h1-3H,9H2

Synthetic route

3-chloro-4-fluoronitrobenzene (350-30-1) → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
With hydrogen In ethanol; water at 25℃; under 760.051 Torr; for 3h; Autoclave;	99.9%
With sodium tetrahydroborate; cyclohexanediamine-Pd-β-cyclodextrin In water at 20℃; for 3h; Sealed tube;	96%
With hydrazine hydrate In ethanol at 100℃; under 760.051 Torr; for 8h; Time; Sealed tube; chemoselective reaction;	94.7%

C14H11ClFNO2 → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
With methanol; sodium tetrahydroborate; nickel(II) chloride hexahydrate at 20℃; for 0.25h; chemoselective reaction;	86%

(3-chloro-4-fluoro-phenyl)-carbamic acid tert-butyl ester (119951-96-1) → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
With methanol; oxalyl dichloride at 20℃; for 2h;	80%

3-Chloronitrobenzene (121-73-3) → 3-chloro-4-fluorophenylamine (367-21-5) + 3-chloro-aniline (108-42-9)

Conditions	Yield
With Piperonyl butoxide; hydrogen fluoride Yields of byproduct given;	A 34% B n/a

1-(3-Chloro-4-fluoro-phenyl)-ethanone oxime → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
(i) PCl5, (ii) aq. HCl; Multistep reaction;

4-Fluoronitrobenzene (350-46-9) → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: iron-powder / Einleiten von Chlor 2: titanium (III)-chloride; water View Scheme
Multi-step reaction with 2 steps 1: Cl2, FeCl3 2: Fe, aq. NH4Cl View Scheme

3-chloro-aniline (108-42-9) → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; sodium nitrite / water / 0.5 h 2: trifluoromethan; fluorosulfonyl fluoride / 70 °C 3: hydrogenchloride / water / 2 h / 50 °C View Scheme

4-fluoro-3-chloronitrosoaniline → 3-chloro-4-fluorophenylamine (367-21-5)

Conditions	Yield
With hydrogenchloride In water at 50℃; for 2h;

3-chloro-4-fluorophenylamine (367-21-5) + diethyl 2-ethoxymethylenemalonate (87-13-8) → diethyl 2-[(3-chloro-4-fluorophenylamino)methylene]malonate (70032-30-3)

Conditions	Yield
at 120 - 130℃; for 2h;	100%
for 0.0333333h; Gould-Jacob reaction; Irradiation;	99%
at 110℃; for 1h; Microwave irradiation;	99%

3-chloro-4-fluorophenylamine (367-21-5) + di-tert-butyl dicarbonate (24424-99-5) → (3-chloro-4-fluoro-phenyl)-carbamic acid tert-butyl ester (119951-96-1)

Conditions	Yield
Stage #1: 3-chloro-4-fluorophenylamine With triethylamine In tetrahydrofuran; water at 20℃; for 0.0833333h; Stage #2: di-tert-butyl dicarbonate In tetrahydrofuran; water at 0 - 20℃; for 6h;	100%
With 1-butyl-3-methylimidazolium trifluoromethanesulfonimide at 30 - 35℃; for 0.25h; neat (no solvent); chemoselective reaction;	95%
In water at 30 - 35℃; for 6h;	92%

3-chloro-4-fluorophenylamine (367-21-5) + 4-chloro-7-fluoro-6-nitroquinazoline (162012-70-6) → N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (162012-67-1)

Conditions	Yield
In isopropyl alcohol for 4h; Product distribution / selectivity; Reflux;	100%
With triethylamine In isopropyl alcohol for 1.5h;	100%
In isopropyl alcohol at 20℃; for 24h; Inert atmosphere;	99%

3-chloro-4-fluorophenylamine (367-21-5) + 4-chloro-6-nitro-7-trifluoromethoxyquinoline-3-carbonitrile (492456-55-0) → 4-(3-chloro-4-fluorophenylamino)-6-nitro-7-trifluoromethoxyquinoline-3-carbonitrile (492456-57-2)

Conditions	Yield
In isopropyl alcohol for 3.5h; Heating;	100%
In ethanol for 12h; Heating;

3-chloro-4-fluorophenylamine (367-21-5) + 6-bromo-4-chloro-3-quinolinecarbonitrile (364793-54-4) → 6-bromo-N-(3-chloro-4-fluoro-phenyl)-quinoline-3-carbnitrile-4-amine (915369-04-9)

Conditions	Yield
In 1,4-dioxane at 90℃; for 2h;	100%
In 1,4-dioxane at 90℃; for 2h;	100%
In 2-ethoxy-ethanol at 135℃; for 2.5h; Heating / reflux;	56%
With aniline In isopropyl alcohol at 80℃; for 24h;	38.8%
In ethanol for 12h; Heating;

3-chloro-4-fluorophenylamine (367-21-5) + 2-chloro-5-methoxyquinoline (160893-07-2) → N-(3-chloro-4-fluorophenyl)-5-methoxyquinolin-2-amine

Conditions	Yield
In neat (no solvent) at 160℃;	100%

1-methyl-piperazine (109-01-3) + 3-chloro-4-fluorophenylamine (367-21-5) + bis(trichloromethyl) carbonate (32315-10-9) → N-(3-chloro-4-fluorophenyl)-4-methylpiperazine-1-carboxamide

Conditions	Yield
Stage #1: 3-chloro-4-fluorophenylamine; bis(trichloromethyl) carbonate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: 1-methyl-piperazine In dichloromethane at 20℃; for 3h;	100%

3-chloro-4-fluorophenylamine (367-21-5) + 2,6-dichloro-4-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine → 6-chloro-N-(3-chloro-4-fluorophenyl)-4-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine

Conditions	Yield
With toluene-4-sulfonic acid In iso-butanol Reflux; Inert atmosphere;	100%

3-chloro-4-fluorophenylamine (367-21-5) + chloroacetyl chloride (79-04-9) → N-(2-chloroacetyl)-3-chloro-4-fluoroaniline (96980-64-2)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 25℃;	99.3%
With triethylamine In dichloromethane at 0 - 25℃;	99.3%
With pyridine In benzene for 1h; Ambient temperature;	90%

3-chloro-4-fluorophenylamine (367-21-5) + 6-acetoxy-4-chloro-7-methoxyquinazoline (230955-75-6) → 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (788136-89-0)

Conditions	Yield
In isopropyl alcohol for 2h; Inert atmosphere; Reflux;	99%
With gold(I) chloride In methanol at 65℃; Reagent/catalyst; Temperature; Concentration;	93.4%
In isopropyl alcohol for 2h; Reflux;	92.5%

3-chloro-4-fluorophenylamine (367-21-5) + 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (199327-59-8) → gefitinib (184475-35-2)

Conditions	Yield
With potassium hydroxide In isopropyl alcohol at 20℃;	99%
In isopropyl alcohol at 80℃; for 0.533333h; Microwave irradiation;	92%
With N,N,N,N,-tetramethylethylenediamine; nickel dichloride In tetrahydrofuran at 50℃; for 0.333333h; Concentration; Temperature; Reagent/catalyst;	92.5%

C11H3ClF3N3O2 + 3-chloro-4-fluorophenylamine (367-21-5) → C17H7ClF4N4O2

Conditions	Yield
In ethanol	99%

3-chloro-4-fluorophenylamine (367-21-5) + 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile (214470-33-4) → 4-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-6-nitro-quinoline-3-carbonitrile (214485-59-3)

Conditions	Yield
Stage #1: 3-chloro-4-fluorophenylamine; 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile In isopropyl alcohol at 20℃; for 22h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	99%
In methanol; 2-methoxy-ethanol; ethyl acetate
In methanol; 2-methoxy-ethanol; ethyl acetate

4-chloro-7-ethoxy-6-nitroquinazoline (936954-10-8) + 3-chloro-4-fluorophenylamine (367-21-5) → N-(3-chloro-4-fluorophenyl)-7-ethoxy-6-nitroquinazoline-4-amine (1360430-70-1)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol Reflux;	99%
In dichloromethane; isopropyl alcohol at 20℃;	93%
In dichloromethane; isopropyl alcohol at 20℃;	93%
In isopropyl alcohol for 1h; Reflux;	89%
With toluene-4-sulfonic acid In isopropyl alcohol at 75℃; for 5h;	76%

4-chloroquinazoline (5190-68-1) + 3-chloro-4-fluorophenylamine (367-21-5) → N-(3-chloro-4-fluorophenyl)quinazolin-4-amine (457932-97-7)

Conditions	Yield
In isopropyl alcohol for 2h; Reflux;	99%
In isopropyl alcohol for 6h; Reflux;	91.6%

3-chloro-4-fluorophenylamine (367-21-5) + C15H13O4Pol → C21H18ClFNO2Pol

Conditions	Yield
Stage #1: 3-chloro-4-fluorophenylamine; C15H13O4Pol With acetic acid In dichloromethane at 20℃; for 2h; not specified; Schlenk technique; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride at 20℃; for 17h; not specified; Schlenk technique;	99%

3-chloro-4-fluorophenylamine (367-21-5) + 4-chloro-7-(3-chloropropoxy)-6-nitroquinoline-3-carbonitrile (501684-28-2) → 4-(3-chloro-4-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-nitro-quinoline-3-carbonitrile (501684-29-3)

Conditions	Yield
In isopropyl alcohol Heating;	98%

3-chloro-4-fluorophenylamine (367-21-5) + 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (3680-69-1) → (3-chloro-4-fluoro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (346600-33-7)

Conditions	Yield
With silver trifluoromethanesulfonate In N,N-dimethyl-formamide at 90℃;	98%

3-chloro-4-fluorophenylamine (367-21-5) + ortho-toluoyl chloride (933-88-0) → N-(3-chloro-4-fluorophenyl)-2-methylbenzamide

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃;	98%

5-amino-4,6-dichloro-2-methylpyrimidine (39906-04-2) + 3-chloro-4-fluorophenylamine (367-21-5) → 6-chloro-N4-(3-chloro-4-fluorophenyl)-2-methylpyrimidine-4,5-diamine

Conditions	Yield
With hydrogenchloride In ethanol; water at 20℃; for 16h; Reflux;	98%

3-chloro-4-fluorophenylamine (367-21-5) + 7-chloro-6-nitro-4(3H)-quinazolinone (53449-14-2) → 4-((3-chloro-4-fluorophenyl)amino)-6-nitro-7-chloroquinazoline (179552-73-9)

Conditions	Yield
Stage #1: 7-chloro-6-nitro-4(3H)-quinazolinone With thionyl chloride In N,N-dimethyl-formamide for 3h; Reflux; Stage #2: 3-chloro-4-fluorophenylamine In 1,4-dioxane; N,N-dimethyl-formamide at 90℃; for 1h;	98%
Stage #1: 7-chloro-6-nitro-4(3H)-quinazolinone With trichlorophosphate In acetonitrile at 80℃; for 5h; Stage #2: 3-chloro-4-fluorophenylamine In 1,4-dioxane; acetonitrile for 1h;	70%

3-chloro-4-fluorophenylamine (367-21-5) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → N-(3-chloro-4-fluoro-phenyl)-formamide (770-22-9)

Conditions	Yield
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 80℃; for 5.5h; Concentration; Inert atmosphere;	98%

3-chloro-4-fluorophenylamine (367-21-5) + Propiolic acid (471-25-0) → N-(3-chloro-4-fluorophenyl)prop-2-ynamide

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 5℃; for 1h;	98%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at -20 - 20℃; for 12h;

formic acid (64-18-6) + 3-chloro-4-fluorophenylamine (367-21-5) → N-(3-chloro-4-fluoro-phenyl)-formamide (770-22-9)

Conditions	Yield
at 80℃; for 3.5h;	97.7%
for 16h; Reflux;	93%
With zinc(II) chloride at 70℃; for 1.33333h; neat (no solvent);	92%

3-chloro-4-fluorophenylamine (367-21-5) + N,N-dimethyl-formamide dimethyl acetal (4637-24-5) → N'-(3-chloro-4-fluorophenyl)-N,N-dimethylmethanimidamide

Conditions	Yield
With acetic anhydride In toluene at 105 - 110℃; for 3h; Time; Reagent/catalyst;	97.4%

3-chloro-4-fluorophenylamine (367-21-5) + isopropyl α-methyl α-diazoacetate (1007586-71-1) → (R)-isopropyl 2-(3-chloro-4-fluorophenylamino)propionate (62836-63-9)

Conditions	Yield
With tetrakis(actonitrile)copper(I) hexafluorophosphate; C35H30N2O2; sodium tetrakis[(3,5-di-trifluoromethyl)phenyl]borate In dichloromethane at 25℃; for 2h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;	97%

3-chloro-4-fluorophenylamine (367-21-5) + 2-amino-5-hydroxy-4-methoxybenzonitrile + N,N-dimethyl-formamide dimethyl acetal (4637-24-5) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
With acetic acid In toluene at 65℃; for 7h; Solvent; Temperature; Concentration; Reagent/catalyst; Inert atmosphere;	97%

3-chloro-4-fluorophenylamine (367-21-5) + benzyl alcohol (100-51-6) → N-(3-chloro-4-fluorophenyl)-benzenemethanamine (131776-32-4)

Conditions	Yield
With palladium nanoparticles embedded in the solid matrix of tetrabutylammonium bromide synthetized in supercritical carbon dioxide at 140℃; Sealed tube; Inert atmosphere; Green chemistry;	97%

4-chloro-6-iodoquinazoline (98556-31-1) + 3-chloro-4-fluorophenylamine (367-21-5) → 4-((3-chloro-4-fluorophenyl)amino)-6-iodoquinazoline (578737-95-8)

Conditions	Yield
In isopropyl alcohol at 80℃; for 2h;	96%
In isopropyl alcohol at 80℃; for 2h;	96.3%
With triethylamine In isopropyl alcohol at 20℃; for 9h; Reflux;	95%
In tetrahydrofuran for 1h; Reflux;	60%
In isopropyl alcohol

Upstream product

• 119951-96-1 (3-chloro-4-fluoro-phenyl)-carbamic acid tert-butyl ester 
• 108-42-9 3-chloro-aniline 
• 350-46-9 4-Fluoronitrobenzene 
• 121-73-3 3-Nitrochlorobenzene 
• 350-30-1 3-chloro-4-fluoronitrobenzene 

Downstream Products

• 137724-66-4 3-chloro-4-fluorophenyl isothiocyanate 
• 150045-48-0 N,N'-Di(3-chloro-4-fluorophenyl)thiourea 
• 305371-33-9 4-(3-chloro-4-fluorophenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile 
• 184475-35-2 gefitinib 
• 96980-64-2 N-(2-chloroacetyl)-3-chloro-4-fluoroaniline 
• 137840-22-3 2-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-benzoic acid 
• 166883-88-1 9-bromo-2-(3-chloro-4-fluorophenyl)-4,4-dimethyl-4,5-dihydropyrrolo[2,3,4-kl]acridin-1(2H)-one 
• 76616-02-9 2,2,2,4,4,4-Hexachloro-1,3-bis-(3-chloro-4-fluoro-phenyl)-2λ⁵,4λ⁵-[1,3,2,4]diazadiphosphetidine 
• 141424-31-9 [4-(3-Chloro-4-fluoro-phenylamino)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]-acetic acid ethyl ester 
• 111658-22-1 [4-(3-Chloro-4-fluoro-phenylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-acetic acid methyl ester 
• 141424-18-2 [4-(3-Chloro-4-fluoro-phenylamino)-5,6-dimethyl-thieno[2,3-d]pyrimidin-2-yl]-acetic acid ethyl ester 
• 128229-97-0 Benzyl N-<2-(4-fluoro-3-chloroanilino)hexafluoro-2-propyl>carbamate 
• 101337-92-2 2-amino-5-chloro-6-fluro[2,1-b][1,3]benzothiazole 
• 101337-93-3 2-amino-6-fluoro-7-chloro-1,3-benzothiazole 

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